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Filz von Reiterdank I, Bento R, Hyun I, Isasi R, Wolf SM, Coert JH, Mink van der Molen AB, Parekkadan B, Uygun K. Designer Organs: Ethical Genetic Modifications in the Era of Machine Perfusion. Annu Rev Biomed Eng 2025; 27:101-128. [PMID: 39874605 DOI: 10.1146/annurev-bioeng-062824-121925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2025]
Abstract
Gene therapy is a rapidly developing field, finally yielding clinical benefits. Genetic engineering of organs for transplantation may soon be an option, thanks to convergence with another breakthrough technology, ex vivo machine perfusion (EVMP). EVMP allows access to the functioning organ for genetic manipulation prior to transplant. EVMP has the potential to enhance genetic engineering efficiency, improve graft survival, and reduce posttransplant complications. This will enable genetic modifications with a vast variety of applications, while raising questions on the ethics and regulation of this emerging technology. This review provides an in-depth discussion of current methodologies for delivering genetic vectors to transplantable organs, particularly focusing on the enabling role of EVMP. Organ-by-organ analysis and key characteristics of various vector and treatment options are assessed. We offer a road map for research and clinical translation, arguing that achieving scientific benchmarks while creating anticipatory governance is necessary to secure societal benefit from this technology.
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Affiliation(s)
- Irina Filz von Reiterdank
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;
- Shriners Children's Boston, Boston, Massachusetts, USA
- Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Raphaela Bento
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;
- Shriners Children's Boston, Boston, Massachusetts, USA
- Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey, USA
| | - Insoo Hyun
- Center for Life Sciences and Public Learning, Boston Museum of Science, Boston, Massachusetts, USA
| | - Rosario Isasi
- Dr. John T. Macdonald Foundation Department of Human Genetics and Institute for Human Genomics, University of Miami School of Medicine, Miami, Florida, USA
| | - Susan M Wolf
- Law School, Medical School, and Consortium on Law and Values in Health, Environment & the Life Sciences, University of Minnesota, Minneapolis, Minnesota, USA
| | - J Henk Coert
- Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Aebele B Mink van der Molen
- Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Biju Parekkadan
- Department of Biomedical Engineering, Rutgers University, Piscataway, New Jersey, USA
| | - Korkut Uygun
- Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;
- Shriners Children's Boston, Boston, Massachusetts, USA
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Filz von Reiterdank I, Mojoudi M, Bento R, Taggart MS, Dinicu AT, Wojtkiewicz G, Coert JH, Mink van der Molen AB, Weissleder R, Parekkadan B, Uygun K. Ex vivo machine perfusion as a platform for lentiviral gene delivery in rat livers. Gene Ther 2025:10.1038/s41434-025-00536-7. [PMID: 40263629 DOI: 10.1038/s41434-025-00536-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 03/28/2025] [Accepted: 04/08/2025] [Indexed: 04/24/2025]
Abstract
Developing new strategies for local monitoring and delivery of immunosuppression is critical to making allografts safer and more accessible. Ex vivo genetic modification of grafts using machine perfusion presents a promising approach to improve graft function and modulate immune responses while minimizing risks of off-target effects and systemic immunogenicity in vivo. This proof-of-concept study demonstrates the feasibility of using normothermic machine perfusion (NMP) to mimic in vitro conditions for effective gene delivery. In this study, lentiviral vectors encoding the secreted biomarker Gaussia Luciferase (GLuc) and red fluorescent protein (RFP) were introduced ex vivo to rodent livers during a 72-h machine perfusion protocol. After an initial 24-h exposure to viral vectors, the organs were maintained in perfusion for an additional 48 h to monitor gene expression, aligning with in vitro benchmarks. Control livers were perfused in similar fashion, but without viral injections. Virally perfused livers exhibited nearly a 10-fold increase in luminescence compared to controls (p < 0.0001), indicating successful genetic modification of the organs. These findings validate the use of machine perfusion systems and viral vectors to genetically engineer whole organs ex vivo, laying the groundwork for a broad range of applications in transplantation through genetic manipulation of organ systems. Future studies will focus on refining this technology to enhance precision in gene expression and explore its implications for clinical translation.
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Affiliation(s)
- Irina Filz von Reiterdank
- Center for Engineering for Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's Boston, Boston, MA, USA
- Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Mohammadreza Mojoudi
- Center for Engineering for Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's Boston, Boston, MA, USA
| | - Raphaela Bento
- Center for Engineering for Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's Boston, Boston, MA, USA
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA
| | - McLean S Taggart
- Center for Engineering for Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's Boston, Boston, MA, USA
| | - Antonia T Dinicu
- Center for Engineering for Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Shriners Children's Boston, Boston, MA, USA
| | - Gregory Wojtkiewicz
- Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - J H Coert
- Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Aebele B Mink van der Molen
- Department of Plastic, Reconstructive and Hand Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Ralph Weissleder
- Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Biju Parekkadan
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA.
| | - Korkut Uygun
- Center for Engineering for Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- Shriners Children's Boston, Boston, MA, USA.
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Harkins L, Vilarinho S, Saltzman WM. Targeting Polymeric Nanoparticles to Specific Cell Populations in the Liver. Biochemistry 2025; 64:1685-1697. [PMID: 40127248 DOI: 10.1021/acs.biochem.4c00712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/26/2025]
Abstract
Nanoparticles (NPs) are beneficial for delivery of drugs in a variety of settings, serving to protect their cargo and allow for sustained release. Polymeric NPs offer several advantages as therapeutics carriers due to their tunable characteristics like size and shape, ease of manufacturing, and biocompatibility. Despite this, there are no polymeric NPs that are approved for treatment of liver diseases. This is surprising since─when administered intravenously─the majority of NPs accumulate in cells in the liver. NP characteristics like size and surface charge can be altered to affect distribution to the liver, and even cellular distribution, but the conjugation of targeting ligands onto the NP surface for specific receptors on the cells is an important approach for enhancing cell specific delivery. Enhancing cell-specific targeting of conjugated NPs in the liver has two major hurdles: 1) avoiding accumulation of NPs in the liver resident macrophages known as Kupffer cells, which are optimized to phagocytose particulates, and 2) overcoming the transport barriers associated with architectural changes of the diseased liver. To identify the structures and mechanisms most important in NP design, NP administration during ex vivo perfusion (EVP)─achieved by anatomically isolating an organ by perfusing it outside the body─may be the most important and efficient approach. However, EVP is currently underutilized in the NP field, with limited research published on NPs delivered during liver EVP, and therefore representing an opportunity for future investigations.
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Affiliation(s)
- Lauren Harkins
- Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06520, United States
| | - Silvia Vilarinho
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut 06520, United States
- Department of Genetics and Pathology, Yale School of Medicine, New Haven, Connecticut 06520, United States
| | - W Mark Saltzman
- Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06520, United States
- Department of Chemical & Environmental Engineering, Yale University, New Haven, Connecticut 06520, United States
- Department of Cellular & Molecular Physiology, Yale University, New Haven, Connecticut 06520, United States
- Department of Dermatology, Yale School of Medicine, New Haven, Connecticut 06520, United States
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Yu JW, Xiang LB, Dong XJ, Yang CX, Wang L, Liu XY, Song YH, Bai XJ, Xiao JW, Ren L, Xu QH, Yang GH, Lv Y, Lu Q. Shortening the recipient warm ischemia time could be a strategy for expanding the liver donor pool. World J Gastroenterol 2025; 31:103188. [PMID: 40061597 PMCID: PMC11886038 DOI: 10.3748/wjg.v31.i9.103188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 01/03/2025] [Accepted: 01/20/2025] [Indexed: 02/18/2025] Open
Abstract
BACKGROUND Shortening the recipient warm ischemia time (rWIT) has been proven to be effective for improving the short- and long-term outcomes after liver transplantation (LT) and offsets the negative impact of an extended cold ischemia time. However, few studies have been conducted to explore the prognostic effects of shortening the rWIT in transplantations using a liver graft from an extended-criteria donor (ECD). AIM To investigate whether shortening the rWIT could improve the outcomes of ECD LT. METHODS Rat ECD autologous orthotopic LT were performed with variable rWITs (0, 10, 20, and 30 minutes). Near-infrared fluorescence imaging (FI) was used for the real-time assessment of liver graft ischemia-reperfusion injury after the anhepatic phase. Survival was assessed, and liver function and histological analyses were performed on the third day after transplantation. RESULTS The FI curve growth rate and postoperative three-day survival rate significantly increased, and the liver function and Suzuki score of the liver grafts significantly improved when the rWIT was ≤ 10 minutes (P < 0.05). CONCLUSION The post-transplant outcomes were significantly better with a shorter rWIT (10 minutes or less) than with a longer rWIT, which could be a strategy for expanding the liver donor pool.
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Affiliation(s)
- Jia-Wei Yu
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Lin-Biao Xiang
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Xiao-Juan Dong
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Chen-Xi Yang
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Lei Wang
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Xiao-Yu Liu
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Yi-Hong Song
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Xian-Jie Bai
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Jing-Wen Xiao
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Lu Ren
- Department of International Medical Center, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Qin-Hong Xu
- Department of Geriatric Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Gang-Hua Yang
- Department of Geriatric Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Yi Lv
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Qiang Lu
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
- Department of Geriatric Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi’an 710061, Shaanxi Province, China
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Pavan-Guimaraes J, Devos L, Lascaris B, de Meijer VE, Monbaliu D, Jochmans I, Pulitano C, Porte RJ, Martins PN. Long-Term Liver Machine Perfusion Preservation: A Review of Recent Advances, Benefits and Logistics. Artif Organs 2025; 49:339-352. [PMID: 39895504 DOI: 10.1111/aor.14941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 12/23/2024] [Indexed: 02/04/2025]
Abstract
BACKGROUND The global shortage of suitable donor livers for transplantation has prompted efforts to expand the donor pool by using extended criteria donors. Machine preservation technology has shown promise in optimizing graft preservation and improving logistics. Additionally, it holds potential for organ repair, regeneration, therapeutic applications during extended preservation periods, and enhancing organ allocation. METHODS We conducted a comprehensive literature review using PubMed, Embase, and Web of Science databases. All studies published between January 1, 2022, and February 7, 2024, that described machine perfusion preservation of livers for more than 24 h were eligible for inclusion. The findings were synthesized in a narrative review format to highlight key benefits and advancements. RESULTS We identified eleven studies from multiple research groups, employing various techniques, devices, and preservation durations. Perfusion durations ranged from 1 to 13 days, with notable variations in protocols for long-term preservation beyond 24 h. Viability was assessed during perfusion only. No livers were transplanted. Among the reviewed studies, the introduction of a dialysis system emerged as the most effective strategy for managing waste accumulation during long-term liver perfusion. Differences were also observed in hemodynamics, oxygenation, organ chambers, supplemental regimens, and glycemic control. CONCLUSION Over the past two years, substantial progress has been made in refining protocols for long-term liver machine perfusion, with significant advancements in waste management, enabling successful multi-day perfusions. While these developments are promising, further research is necessary to standardize and optimize long-term perfusion protocols, establishing a reliable platform for both organ preservation and therapeutic applications.
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Affiliation(s)
| | - Lene Devos
- Department of Microbiology, Immunology and Transplantation, Transplantation Research Group, Lab of Abdominal Transplantation, KU Leuven, Leuven, Belgium
| | - Bianca Lascaris
- Section of HPB Surgery and Liver Transplantation, UMCG Comprehensive Transplant Center, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Vincent E de Meijer
- Section of HPB Surgery and Liver Transplantation, UMCG Comprehensive Transplant Center, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands
| | - Diethard Monbaliu
- Department of Microbiology, Immunology and Transplantation, Transplantation Research Group, Lab of Abdominal Transplantation, KU Leuven, Leuven, Belgium
- Abdominal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Ina Jochmans
- Department of Microbiology, Immunology and Transplantation, Transplantation Research Group, Lab of Abdominal Transplantation, KU Leuven, Leuven, Belgium
- Abdominal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Carlo Pulitano
- Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Robert J Porte
- Division of HPB and Transplant Surgery, Erasmus MC Transplant Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Paulo N Martins
- Department of Surgery, Transplant Institute, University of Oklahoma, Oklahoma City, Oklahoma, USA
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Deng S, Zhang Y, Shen S, Li C, Qin C. Immunometabolism of Liver Xenotransplantation and Prospective Solutions. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2407610. [PMID: 39912334 PMCID: PMC11884532 DOI: 10.1002/advs.202407610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 10/26/2024] [Indexed: 02/07/2025]
Abstract
End-stage liver diseases, such as hepatocellular carcinoma or acute liver failure, critically necessitate liver transplantation. However, the shortage of available organ donors fails to meet the rapidly growing transplantation demand. Due to the high similarity of liver tissue structure and metabolism between miniature pigs and humans, xenotransplantation of pig livers is considered as a potentially viable solution to organ scarcity. In the 2024, teams from China first time have successfully transplanted a genetically modified Bama miniature pig liver into a clinically brain-dead man lasting for 10 days. This milestone in human xenotransplantation research not only confirms the feasibility of clinical application of xenotransplantation, but also underscores the daunting and protracted nature of this pathway. Despite advanced gene-editing technologies theoretically circumventing the occurrence of most transplant rejection reactions, patients still face challenges such as chronic immune rejection, coagulation disorders, and thrombotic microangiopathy after receiving xenografts. Moreover, prolonged use of immunosuppressive drugs may induce irreversible immune dysfunction, leading to opportunistic infections and metabolic disorders. This article compares the similarities and differences in livers between humans and pigs, summarizes the immunometabolism of xenotransplantation based on current findings, and provides research perspectives on pre-transplantation and post-transplantation strategies for prolonging the survival time of xenografts.
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Affiliation(s)
- Shoulong Deng
- National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, National Health Commission of China (NHC) Key Laboratory of Comparative Medicine, Institute of Laboratory Animal SciencesChinese Academy of Medical Sciences and Comparative Medicine CenterPeking Union Medical CollegeBeijing100021China
| | - Yi Zhang
- Department of MedicinePanzhihua UniversitySichuan61700China
| | - Shasha Shen
- Department of MedicinePanzhihua UniversitySichuan61700China
| | - Chongyang Li
- Institute of Animal SciencesChinese Academy of Agricultural SciencesBeijing100193China
| | - Chuan Qin
- National Center of Technology Innovation for Animal Model, National Human Diseases Animal Model Resource Center, National Health Commission of China (NHC) Key Laboratory of Comparative Medicine, Institute of Laboratory Animal SciencesChinese Academy of Medical Sciences and Comparative Medicine CenterPeking Union Medical CollegeBeijing100021China
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Uygun K, von Reiterdank IF, Mojoudi M, Bento R, Taggart M, Dinicu A, Wojtkiewicz G, Coert J, van der Molen AM, Weissleder R, Parekkadan B. Ex Vivo Machine Perfusion as a Platform for Lentiviral Gene Delivery in Rat Livers. RESEARCH SQUARE 2024:rs.3.rs-4784505. [PMID: 39315250 PMCID: PMC11419271 DOI: 10.21203/rs.3.rs-4784505/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
Developing new strategies for local monitoring and delivery of immunosuppression is critical to making allografts safer and more accessible. Ex vivo genetic modification of grafts using machine perfusion presents a promising approach to improve graft function and modulate immune responses while minimizing risks of off-target effects and systemic immunogenicity in vivo. This proof-of-concept study demonstrates the feasibility of using normothermic machine perfusion (NMP) to mimic in vitro conditions for effective gene delivery. In this study, lentiviral vectors carrying biosensor constructs with Gaussia Luciferase (GLuc) were introduced to rodent livers during a 72-hour perfusion period, with a targeted delivery of 3 × 107 infection units (IU). Following the initial 24-hour exposure required for viral transduction, an additional 48 hours was necessary to observe gene expression, analogous to in vitro benchmarks. The perfused livers displayed significantly increased luminescence compared to controls, illustrating successful genetic modification. These findings validate the ex vivo use of lentiviral particles in a rodent liver model and lay the groundwork for a broad range of applications through genetic manipulation of organ systems. Future studies will focus on refining this technology to enhance precision in gene expression and explore its implications for clinical transplantation.
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Affiliation(s)
- Korkut Uygun
- Massachusetts General Hospital, Harvard Medical School
| | | | | | | | | | | | | | - J Coert
- University Medical Center Utrecht
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Broere R, Luijmes SH, de Jonge J, Porte RJ. Graft repair during machine perfusion: a current overview of strategies. Curr Opin Organ Transplant 2024; 29:248-254. [PMID: 38726753 PMCID: PMC11224572 DOI: 10.1097/mot.0000000000001151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/03/2024]
Abstract
PURPOSE OF REVIEW With changing donor characteristics (advanced age, obesity), an increase in the use of extended criteria donor (ECD) livers in liver transplantation is seen. Machine perfusion allows graft viability assessment, but still many donor livers are considered nontransplantable. Besides being used as graft viability assessment tool, ex situ machine perfusion offers a platform for therapeutic strategies to ameliorate grafts prior to transplantation. This review describes the current landscape of graft repair during machine perfusion. RECENT FINDINGS Explored anti-inflammatory therapies, including inflammasome inhibitors, hemoabsorption, and cellular therapies mitigate the inflammatory response and improve hepatic function. Cholangiocyte organoids show promise in repairing the damaged biliary tree. Defatting during normothermic machine perfusion shows a reduction of steatosis and improved hepatobiliary function compared to nontreated livers. Uptake of RNA interference therapies during machine perfusion paves the way for an additional treatment modality. SUMMARY The possibility to repair injured donor livers during ex situ machine perfusion might increase the utilization of ECD-livers. Application of defatting agents is currently explored in clinical trials, whereas other therapeutics require further research or optimization before entering clinical research.
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Affiliation(s)
- Roberto Broere
- Department of Surgery, Division of Hepato-Pancreato- Biliary and Transplant Surgery, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
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Risbey CWG, Lau NS, Niu A, Zhang WB, Crawford M, Pulitano C. Return of the cold: How hypothermic oxygenated machine perfusion is changing liver transplantation. Transplant Rev (Orlando) 2024; 38:100853. [PMID: 38581881 DOI: 10.1016/j.trre.2024.100853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 03/28/2024] [Accepted: 04/01/2024] [Indexed: 04/08/2024]
Abstract
Hypothermic Oxygenated machine PErfusion (HOPE) has recently emerged as a preservation technique which can reduce ischemic injury and improve clinical outcomes following liver transplantation. First developed with the advent solid organ transplantation techniques, hypothermic machine perfusion largely fell out of favour following the development of preservation solutions which can satisfactorily preserve grafts using the cheap and simple method, static cold storage (SCS). However, with an increasing need to develop techniques to reduce graft injury and better utilise marginal and donation after circulatory death (DCD) grafts, HOPE has emerged as a relatively simple and safe technique to optimise clinical outcomes following liver transplantation. Perfusing the graft with cold, acellular, oxygenated perfusate either via the portal vein (PV) alone, or via both the PV and hepatic artery (HA), HOPE is generally commenced for a period of 1-2 h immediately prior to implantation. The technique has been validated by multiple randomised control trials, and pre-clinical evidence suggests HOPE primarily reduces graft injury by decreasing the accumulation of harmful mitochondrial intermediates, and subsequently, the severity of post-reperfusion injury. HOPE can also facilitate real time graft assessment, most notably via the measurement of flavin mononucleotide (FMN) in the perfusate, allowing transplant teams to make better informed clinical decisions prior to transplantation. HOPE may also provide a platform to administer novel therapeutic agents to ex situ organs without risk of systemic side effects. As such, HOPE is uniquely positioned to revolutionise how liver transplantation is approached and facilitate optimised clinical outcomes for liver transplant recipients.
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Affiliation(s)
- Charles W G Risbey
- Department of Transplant Surgery, Royal Prince Alfred Hospital, 50 Missenden Rd, Camperdown 2050, NSW, Australia; Centre for Organ Assessment, Repair, & Optimization (COARO), 145 Missenden Rd, Camperdown 2050, NSW, Australia; Royal Prince Alfred Hospital Transplant Institute (RPATI), 145 Missenden Rd, Camperdown 2050, NSW, Australia; Central Clinical School, The University of Sydney, John Hopkins Dr, Camperdown 2050, NSW, Australia
| | - Ngee-Soon Lau
- Department of Transplant Surgery, Royal Prince Alfred Hospital, 50 Missenden Rd, Camperdown 2050, NSW, Australia; Centre for Organ Assessment, Repair, & Optimization (COARO), 145 Missenden Rd, Camperdown 2050, NSW, Australia; Royal Prince Alfred Hospital Transplant Institute (RPATI), 145 Missenden Rd, Camperdown 2050, NSW, Australia
| | - Anita Niu
- Department of Transplant Surgery, Royal Prince Alfred Hospital, 50 Missenden Rd, Camperdown 2050, NSW, Australia; Centre for Organ Assessment, Repair, & Optimization (COARO), 145 Missenden Rd, Camperdown 2050, NSW, Australia; Royal Prince Alfred Hospital Transplant Institute (RPATI), 145 Missenden Rd, Camperdown 2050, NSW, Australia
| | - Wesley B Zhang
- Centre for Organ Assessment, Repair, & Optimization (COARO), 145 Missenden Rd, Camperdown 2050, NSW, Australia
| | - Michael Crawford
- Department of Transplant Surgery, Royal Prince Alfred Hospital, 50 Missenden Rd, Camperdown 2050, NSW, Australia; Centre for Organ Assessment, Repair, & Optimization (COARO), 145 Missenden Rd, Camperdown 2050, NSW, Australia; Royal Prince Alfred Hospital Transplant Institute (RPATI), 145 Missenden Rd, Camperdown 2050, NSW, Australia; Central Clinical School, The University of Sydney, John Hopkins Dr, Camperdown 2050, NSW, Australia
| | - Carlo Pulitano
- Department of Transplant Surgery, Royal Prince Alfred Hospital, 50 Missenden Rd, Camperdown 2050, NSW, Australia; Centre for Organ Assessment, Repair, & Optimization (COARO), 145 Missenden Rd, Camperdown 2050, NSW, Australia; Royal Prince Alfred Hospital Transplant Institute (RPATI), 145 Missenden Rd, Camperdown 2050, NSW, Australia; Central Clinical School, The University of Sydney, John Hopkins Dr, Camperdown 2050, NSW, Australia.
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Chullo G, Panisello-Rosello A, Marquez N, Colmenero J, Brunet M, Pera M, Rosello-Catafau J, Bataller R, García-Valdecasas JC, Fundora Y. Focusing on Ischemic Reperfusion Injury in the New Era of Dynamic Machine Perfusion in Liver Transplantation. Int J Mol Sci 2024; 25:1117. [PMID: 38256190 PMCID: PMC10816079 DOI: 10.3390/ijms25021117] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 01/04/2024] [Accepted: 01/08/2024] [Indexed: 01/24/2024] Open
Abstract
Liver transplantation is the most effective treatment for end-stage liver disease. Transplant indications have been progressively increasing, with a huge discrepancy between the supply and demand of optimal organs. In this context, the use of extended criteria donor grafts has gained importance, even though these grafts are more susceptible to ischemic reperfusion injury (IRI). Hepatic IRI is an inherent and inevitable consequence of all liver transplants; it involves ischemia-mediated cellular damage exacerbated upon reperfusion and its severity directly affects graft function and post-transplant complications. Strategies for organ preservation have been constantly improving since they first emerged. The current gold standard for preservation is perfusion solutions and static cold storage. However, novel approaches that allow extended preservation times, organ evaluation, and their treatment, which could increase the number of viable organs for transplantation, are currently under investigation. This review discusses the mechanisms associated with IRI, describes existing strategies for liver preservation, and emphasizes novel developments and challenges for effective organ preservation and optimization.
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Affiliation(s)
- Gabriela Chullo
- Service of Digestive, Hepato-Pancreatico-Biliary and Liver Transplant Surgery, Institut Clínic de Malalties Digestives i Metabòliques (ICMDM), Hospital Clinic of Barcelona, 08036 Barcelona, Spain; (G.C.); (M.P.); (J.C.G.-V.)
- Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (J.C.); (M.B.); (R.B.)
| | - Arnau Panisello-Rosello
- Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (J.C.); (M.B.); (R.B.)
| | - Noel Marquez
- Hepato-Pancreatico-Biliary and Liver Transplant Surgery, Institut Clínic de Malalties Digestives i Metabòliques (ICMDM), Hospital Clinic of Barcelona, 08036 Barcelona, Spain;
| | - Jordi Colmenero
- Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (J.C.); (M.B.); (R.B.)
- Liver Transplant Unit, Service of Hepatology, Institut Clínic de Malalties Digestives i Metabòliques (ICMDM), Hospital Clinic of Barcelona, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades hepaticas y digestives (CIBERehd), University of Barcelona, 08036 Barcelona, Spain
| | - Merce Brunet
- Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (J.C.); (M.B.); (R.B.)
- Centro de Investigación Biomédica en Red de Enfermedades hepaticas y digestives (CIBERehd), University of Barcelona, 08036 Barcelona, Spain
- Pharmacology and Toxicology Laboratory, Biochemistry and Molecular Genetics Department, Biomedical Diagnostic Center, Hospital Clinic of Barcelona, 08036 Barcelona, Spain
| | - Miguel Pera
- Service of Digestive, Hepato-Pancreatico-Biliary and Liver Transplant Surgery, Institut Clínic de Malalties Digestives i Metabòliques (ICMDM), Hospital Clinic of Barcelona, 08036 Barcelona, Spain; (G.C.); (M.P.); (J.C.G.-V.)
- Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (J.C.); (M.B.); (R.B.)
| | - Joan Rosello-Catafau
- Experimental Pathology, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Científicas (IBB-CSIC), 08036 Barcelona, Spain;
| | - Ramon Bataller
- Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (J.C.); (M.B.); (R.B.)
- Liver Transplant Unit, Service of Hepatology, Institut Clínic de Malalties Digestives i Metabòliques (ICMDM), Hospital Clinic of Barcelona, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades hepaticas y digestives (CIBERehd), University of Barcelona, 08036 Barcelona, Spain
| | - Juan Carlos García-Valdecasas
- Service of Digestive, Hepato-Pancreatico-Biliary and Liver Transplant Surgery, Institut Clínic de Malalties Digestives i Metabòliques (ICMDM), Hospital Clinic of Barcelona, 08036 Barcelona, Spain; (G.C.); (M.P.); (J.C.G.-V.)
- Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (J.C.); (M.B.); (R.B.)
| | - Yiliam Fundora
- Service of Digestive, Hepato-Pancreatico-Biliary and Liver Transplant Surgery, Institut Clínic de Malalties Digestives i Metabòliques (ICMDM), Hospital Clinic of Barcelona, 08036 Barcelona, Spain; (G.C.); (M.P.); (J.C.G.-V.)
- Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain; (J.C.); (M.B.); (R.B.)
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11
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Griffiths C, Scott WE, Ali S, Fisher AJ. Maximizing organs for donation: the potential for ex situ normothermic machine perfusion. QJM 2023; 116:650-657. [PMID: 31943119 DOI: 10.1093/qjmed/hcz321] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 12/13/2019] [Accepted: 12/16/2019] [Indexed: 11/13/2022] Open
Abstract
Currently, there is a shortfall in the number of suitable organs available for transplant resulting in a high number of patients on the active transplant waiting lists worldwide. To address this shortfall and increase the utilization of donor organs, the acceptance criteria for donor organs is gradually expanding including increased use of organs from donation after circulatory death. Use of such extended criteria donors and exposure of organs to more prolonged periods of warm or cold ischaemia also increases the risk of primary graft dysfunction occurring. Normothermic machine perfusion (NMP) offers a unique opportunity to objectively assess donor organ function outside the donor body and potentially recondition those deemed unsuitable on initial evaluation prior to implantation in the recipient. Furthermore, NMP provides a platform to support the use of established and novel therapeutics delivered directly to the organ, without the need to worry about potential deleterious 'off-target' side effects typically considered when treating the whole patient. This review will explore some of the novel therapeutics currently being added to perfusion platforms during NMP experimentally in an attempt to improve organ function and post-transplant outcomes.
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Affiliation(s)
- C Griffiths
- From the NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, Institute of Transplantation, Freeman Hospital, Newcastle Upon Tyne, NE7 7DN, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK
| | - W E Scott
- From the NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, Institute of Transplantation, Freeman Hospital, Newcastle Upon Tyne, NE7 7DN, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK
| | - S Ali
- From the NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, Institute of Transplantation, Freeman Hospital, Newcastle Upon Tyne, NE7 7DN, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK
| | - A J Fisher
- From the NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, Institute of Transplantation, Freeman Hospital, Newcastle Upon Tyne, NE7 7DN, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, NE2 4HH, UK
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12
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Sitbon A, Delmotte PR, Goumard C, Turco C, Gautheron J, Conti F, Aoudjehane L, Scatton O, Monsel A. Therapeutic potentials of mesenchymal stromal cells-derived extracellular vesicles in liver failure and marginal liver graft rehabilitation: a scoping review. Minerva Anestesiol 2023; 89:690-706. [PMID: 37079286 DOI: 10.23736/s0375-9393.23.17265-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/21/2023]
Abstract
Liver failure includes distinct subgroups of diseases: Acute liver failure (ALF) without preexisting cirrhosis, acute-on-chronic liver failure (ACLF) (severe form of cirrhosis associated with organ failures and excess mortality), and liver fibrosis (LF). Inflammation plays a key role in ALF, LF, and more specifically in ACLF for which we have currently no treatment other than liver transplantation (LT). The increasing incidence of marginal liver grafts and the shortage of liver grafts require us to consider strategies to increase the quantity and quality of available liver grafts. Mesenchymal stromal cells (MSCs) have shown beneficial pleiotropic properties with limited translational potential due to the pitfalls associated with their cellular nature. MSC-derived extracellular vesicles (MSC-EVs) are innovative cell-free therapeutics for immunomodulation and regenerative purposes. MSC-EVs encompass further advantages: pleiotropic effects, low immunogenicity, storage stability, good safety profile, and possibility of bioengineering. Currently, no human studies explored the impact of MSC-EVs on liver disease, but several preclinical studies highlighted their beneficial effects. In ALF and ACLF, data showed that MSC-EVs attenuate hepatic stellate cells activation, exert antioxidant, anti-inflammatory, anti-apoptosis, anti-ferroptosis properties, and promote regeneration of the liver, autophagy, and improve metabolism through mitochondrial function recovery. In LF, MSC-EVs demonstrated anti-fibrotic properties associated with liver tissue regeneration. Normothermic-machine perfusion (NMP) combined with MSC-EVs represents an attractive therapy to improve liver regeneration before LT. Our review suggests a growing interest in MSC-EVs in liver failure and gives an appealing insight into their development to rehabilitate marginal liver grafts through NMP.
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Affiliation(s)
- Alexandre Sitbon
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France -
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France -
| | - Pierre-Romain Delmotte
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
| | - Claire Goumard
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- Department of Digestive, Hepatobiliary Surgery and Liver Transplantation, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
| | - Célia Turco
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- Liver Transplantation Unit, Department of Digestive and Oncologic Surgery, University Hospital of Besançon, Besançon, France
| | - Jérémie Gautheron
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
| | - Filomena Conti
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- Department of Digestive, Hepatobiliary Surgery and Liver Transplantation, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
- IHU-Innovation of Cardiometabolism and Nutrition (ICAN), INSERM, Sorbonne University, Paris, France
| | - Lynda Aoudjehane
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- IHU-Innovation of Cardiometabolism and Nutrition (ICAN), INSERM, Sorbonne University, Paris, France
| | - Olivier Scatton
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- Department of Digestive, Hepatobiliary Surgery and Liver Transplantation, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
| | - Antoine Monsel
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
- INSERM UMRS-959 Immunology-Immunopathology-Immunotherapy (I3), Sorbonne University, Paris, France
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13
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Banker A, Bhatt N, Rao PS, Agrawal P, Shah M, Nayak M, Mohanka R. A Review of Machine Perfusion Strategies in Liver Transplantation. J Clin Exp Hepatol 2023; 13:335-349. [PMID: 36950485 PMCID: PMC10025749 DOI: 10.1016/j.jceh.2022.08.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/26/2022] [Accepted: 08/02/2022] [Indexed: 02/17/2023] Open
Abstract
The acceptance of liver transplantation as the standard of care for end-stage liver diseases has led to a critical shortage of donor allografts. To expand the donor organ pool, many countries have liberalized the donor criteria including extended criteria donors and donation after circulatory death. These marginal livers are at a higher risk of injury when they are preserved using the standard static cold storage (SCS) preservation techniques. In recent years, research has focused on optimizing organ preservation techniques to protect these marginal livers. Machine perfusion (MP) of the expanded donor liver has witnessed considerable advancements in the last decade. Research has showed MP strategies to confer significant advantages over the SCS techniques, such as longer preservation times, viability assessment and the potential to recondition high risk allografts prior to implantation. In this review article, we address the topic of MP in liver allograft preservation, with emphasis on current trends in clinical application. We discuss the relevant clinical trials related to the techniques of hypothermic MP, normothermic MP, hypothermic oxygenated MP, and controlled oxygenated rewarming. We also discuss the potential applications of ex vivo therapeutics which may be relevant in the future to further optimize the allograft prior to transplantation.
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Key Words
- ALP, Alkaline phosphatase
- ALT, Alanine transaminase
- ASO, Antisense oligonucleotides
- AST, Aspartate transaminase
- CIT, Cold ischemia times
- COPE, Consortium for Organ Preservation in Europe
- COR, Controlled oxygenated rewarming
- DBD, Donation after brain death
- DCD, Donation after circulatory death
- DHOPE, dual hypothermic oxygenated machine perfusion
- EAD, Early allograft dysfunction
- ECD, Extended criteria donors
- ETC, Electron transport chain
- GGT, Gamma glutamyl transferase
- HCV, Hepatitis C virus
- HMP, Hypothermic machine perfusion
- HOPE, Hypothermic oxygenated machine perfusion
- ICU, Intensive care unit
- IGL, Institute George Lopez-1
- INR, International normalized ratio
- IRI, ischemia reperfusion injury
- LDH, Lactate dehydrogenase
- MELD, Model for end-stage liver disease
- MP, Machine perfusion
- NAS, Non-anastomotic biliary strictures
- NMP, Normothermic machine perfusion
- NO, Nitric oxide
- PNF, Primary nonfunction
- ROS, Reactive oxygen species
- RT-PCR, Reverse transcription polymerase chain reaction
- SNMP, Sub-normothermic machine perfusion
- UW, University of Wisconsin
- WIT, Warm ischemia times
- hypothermic machine perfusion
- hypothermic oxygenated machine perfusion
- machine perfusion
- normothermic machine perfusion
- static cold storage
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Affiliation(s)
- Amay Banker
- Department of Liver Transplant and HPB Surgery, Sir HN Reliance Foundation Hospital, Mumbai, India
| | - Neha Bhatt
- Department of Liver Transplant and HPB Surgery, Sir HN Reliance Foundation Hospital, Mumbai, India
| | - Prashantha S. Rao
- Department of Liver Transplant and HPB Surgery, Sir HN Reliance Foundation Hospital, Mumbai, India
| | - Pravin Agrawal
- Department of Liver Transplant and HPB Surgery, Sir HN Reliance Foundation Hospital, Mumbai, India
| | - Mitul Shah
- Department of Liver Transplant and HPB Surgery, Sir HN Reliance Foundation Hospital, Mumbai, India
| | - Madhavi Nayak
- Department of Liver Transplant and HPB Surgery, Sir HN Reliance Foundation Hospital, Mumbai, India
| | - Ravi Mohanka
- Department of Liver Transplant and HPB Surgery, Sir HN Reliance Foundation Hospital, Mumbai, India
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14
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Lin Y, Huang H, Chen L, Chen R, Liu J, Zheng S, Ling Q. Assessing Donor Liver Quality and Restoring Graft Function in the Era of Extended Criteria Donors. J Clin Transl Hepatol 2023; 11:219-230. [PMID: 36406331 PMCID: PMC9647107 DOI: 10.14218/jcth.2022.00194] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 06/23/2022] [Accepted: 07/20/2022] [Indexed: 12/04/2022] Open
Abstract
Liver transplantation (LT) is the final treatment option for patients with end-stage liver disease. The increasing donor shortage results in the wide usage of grafts from extended criteria donors across the world. Using such grafts is associated with the elevated incidences of post-transplant complications including initial nonfunction and ischemic biliary tract diseases, which significantly reduce recipient survival. Although several clinical factors have been demonstrated to impact donor liver quality, accurate, comprehensive, and effective assessment systems to guide decision-making for organ usage, restoration or discard are lacking. In addition, the development of biochemical technologies and bioinformatic analysis in recent years helps us better understand graft injury during the perioperative period and find potential ways to restore graft function. Moreover, such advances reveal the molecular profiles of grafts or perfusate that are susceptible to poor graft function and provide insight into finding novel biomarkers for graft quality assessment. Focusing on donors and grafts, we updated potential biomarkers in donor blood, liver tissue, or perfusates that predict graft quality following LT, and summarized strategies for restoring graft function in the era of extended criteria donors. In this review, we also discuss the advantages and drawbacks of these potential biomarkers and offer suggestions for future research.
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Affiliation(s)
- Yimou Lin
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Haitao Huang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Lifeng Chen
- Department of Clinical Engineering and Information Technology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Ruihan Chen
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jimin Liu
- Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Shusen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Combined Multiorgan Transplantation, Ministry of Public Health, Hangzhou, Zhejiang, China
| | - Qi Ling
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Combined Multiorgan Transplantation, Ministry of Public Health, Hangzhou, Zhejiang, China
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15
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Lascaris B, de Meijer VE, Porte RJ. Normothermic liver machine perfusion as a dynamic platform for regenerative purposes: What does the future have in store for us? J Hepatol 2022; 77:825-836. [PMID: 35533801 DOI: 10.1016/j.jhep.2022.04.033] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 04/19/2022] [Accepted: 04/27/2022] [Indexed: 01/06/2023]
Abstract
Liver transplantation has become an immense success; nevertheless, far more recipients are registered on waiting lists than there are available donor livers for transplantation. High-risk, extended criteria donor livers are increasingly used to reduce the discrepancy between organ demand and supply. Especially for high-risk livers, dynamic preservation using machine perfusion can decrease post-transplantation complications and may increase donor liver utilisation by improving graft quality and enabling viability testing before transplantation. To further increase the availability of donor livers suitable for transplantation, new strategies are required that make it possible to use organs that are initially too damaged to be transplanted. With the current progress in experimental liver transplantation research, (long-term) normothermic machine perfusion may be used in the future as a dynamic platform for regenerative medicine approaches, enabling repair and regeneration of injured donor livers. Currently explored therapeutics such as defatting cocktails, RNA interference, senolytics, and stem cell therapy may assist in the repair and/or regeneration of injured livers before transplantation. This review will provide a forecast of the future utility of normothermic machine perfusion in decreasing the imbalance between donor liver demand and supply by enabling the repair and regeneration of damaged donor livers.
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Affiliation(s)
- Bianca Lascaris
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Vincent E de Meijer
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Robert J Porte
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
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16
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Panconesi R, Flores Carvalho M, Dondossola D, Muiesan P, Dutkowski P, Schlegel A. Impact of Machine Perfusion on the Immune Response After Liver Transplantation - A Primary Treatment or Just a Delivery Tool. Front Immunol 2022; 13:855263. [PMID: 35874758 PMCID: PMC9304705 DOI: 10.3389/fimmu.2022.855263] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 05/31/2022] [Indexed: 12/12/2022] Open
Abstract
The frequent use of marginal livers forces transplant centres to explore novel technologies to improve organ quality and outcomes after implantation. Organ perfusion techniques are therefore frequently discussed with an ever-increasing number of experimental and clinical studies. Two main approaches, hypothermic and normothermic perfusion, are the leading strategies to be introduced in clinical practice in many western countries today. Despite this success, the number of studies, which provide robust data on the underlying mechanisms of protection conveyed through this technology remains scarce, particularly in context of different stages of ischemia-reperfusion-injury (IRI). Prior to a successful clinical implementation of machine perfusion, the concept of IRI and potential key molecules, which should be addressed to reduce IRI-associated inflammation, requires a better exploration. During ischemia, Krebs cycle metabolites, including succinate play a crucial role with their direct impact on the production of reactive oxygen species (ROS) at mitochondrial complex I upon reperfusion. Such features are even more pronounced under normothermic conditions and lead to even higher levels of downstream inflammation. The direct consequence appears with an activation of the innate immune system. The number of articles, which focus on the impact of machine perfusion with and without the use of specific perfusate additives to modulate the inflammatory cascade after transplantation is very small. This review describes first, the subcellular processes found in mitochondria, which instigate the IRI cascade together with proinflammatory downstream effects and their link to the innate immune system. Next, the impact of currently established machine perfusion strategies is described with a focus on protective mechanisms known for the different perfusion approaches. Finally, the role of such dynamic preservation techniques to deliver specific agents, which appear currently of interest to modulate this posttransplant inflammation, is discussed together with future aspects in this field.
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Affiliation(s)
- Rebecca Panconesi
- Department of Clinical and Experimental Medicine, Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy
- General Surgery 2U-Liver Transplant Unit, Department of Surgery, A.O.U. Città della Salute e della, Scienza di Torino, University of Turin, Turin, Italy
| | - Mauricio Flores Carvalho
- Department of Clinical and Experimental Medicine, Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy
| | - Daniele Dondossola
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore, Policlinico and University of Milan, Milan, Italy
| | - Paolo Muiesan
- Department of Clinical and Experimental Medicine, Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore, Policlinico and University of Milan, Milan, Italy
| | - Philipp Dutkowski
- Department of Surgery and Transplantation, Swiss Hepato-Pancreato-Biliary (HPB) Center, University Hospital Zurich, Zurich, Switzerland
| | - Andrea Schlegel
- Department of Clinical and Experimental Medicine, Hepatobiliary Unit, Careggi University Hospital, University of Florence, Florence, Italy
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore, Policlinico and University of Milan, Milan, Italy
- Department of Surgery and Transplantation, Swiss Hepato-Pancreato-Biliary (HPB) Center, University Hospital Zurich, Zurich, Switzerland
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17
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Abstract
In a recent paper, Clavien et al. demonstrate the successful transplant of a sub-optimal donor liver using multi-day normothermic machine perfusion. This technological milestone opens up exciting new avenues for liver transplantation with the potential to ameliorate donor organ shortages and permit targeted therapeutic interventions.
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Affiliation(s)
- Alexander Sagar
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - Peter Friend
- Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.
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18
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Del Turco S, Cappello V, Tapeinos C, Moscardini A, Sabatino L, Battaglini M, Melandro F, Torri F, Martinelli C, Babboni S, Silvestrini B, Morganti R, Gemmi M, De Simone P, Martins PN, Crocetti L, Peris A, Campani D, Basta G, Ciofani G, Ghinolfi D. Cerium oxide nanoparticles administration during machine perfusion of discarded human livers: A pilot study. Liver Transpl 2022; 28:1173-1185. [PMID: 35100468 DOI: 10.1002/lt.26421] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 01/10/2022] [Accepted: 01/20/2022] [Indexed: 01/13/2023]
Abstract
The combined approach of ex situ normothermic machine perfusion (NMP) and nanotechnology represents a strategy to mitigate ischemia/reperfusion injury in liver transplantation (LT). We evaluated the uptake, distribution, and efficacy of antioxidant cerium oxide nanoparticles (nanoceria) during normothermic perfusion of discarded human livers. A total of 9 discarded human liver grafts were randomized in 2 groups and underwent 4 h of NMP: 5 grafts were treated with nanoceria conjugated with albumin (Alb-NC; 50 µg/ml) and compared with 4 untreated grafts. The intracellular uptake of nanoceria was analyzed by electron microscopy (EM) and inductively coupled plasma-mass spectrometry (ICP-MS). The antioxidant activity of Alb-NC was assayed in liver biopsies by glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) assay, telomere length, and 4977-bp common mitochondrial DNA deletion (mtDNA4977 deletion). The cytokine profile was evaluated in perfusate samples. EM and ICP-MS confirmed Alb-NC internalization, rescue of mitochondrial phenotype, decrease of lipid droplet peroxidation, and lipofuscin granules in the treated grafts. Alb-NC exerted an antioxidant activity by increasing GSH levels (percentage change: +94% ± 25%; p = 0.01), SOD (+17% ± 4%; p = 0.02), and CAT activity (51% ± 23%; p = 0.03), reducing the occurrence of mtDNA4977 deletion (-67.2% ± 11%; p = 0.03), but did not affect cytokine release. Alb-NC during ex situ perfusion decreased oxidative stress, upregulating graft antioxidant defense. They could be a tool to improve quality grafts during NMP and represent an antioxidant strategy aimed at protecting the graft against reperfusion injury during LT.
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Affiliation(s)
- Serena Del Turco
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Valentina Cappello
- Center for Materials Interfaces, Electron Crystallography, Istituto Italiano di Tecnologia, Pontedera, Italy
| | - Christos Tapeinos
- Smart Bio-Interfaces, Istituto Italiano di Tecnologia, Pontedera, Italy
| | - Aldo Moscardini
- National Enterprise for nanoScience and nanoTechnology, Scuola Normale Superiore, Pisa, Italy
| | - Laura Sabatino
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Matteo Battaglini
- Smart Bio-Interfaces, Istituto Italiano di Tecnologia, Pontedera, Italy
| | - Fabio Melandro
- Division of Hepatic Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - Francesco Torri
- Division of Hepatic Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - Caterina Martinelli
- Division of Hepatic Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - Serena Babboni
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Beatrice Silvestrini
- Division of Interventional Radiology, University of Pisa Medical School Hospital, Pisa, Italy
| | | | - Mauro Gemmi
- Center for Materials Interfaces, Electron Crystallography, Istituto Italiano di Tecnologia, Pontedera, Italy
| | - Paolo De Simone
- Division of Hepatic Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
| | - Paulo N Martins
- Department of Surgery, Division of Transplantation, University of Massachusetts, Worcester, Massachusetts, USA
| | - Laura Crocetti
- Division of Interventional Radiology, University of Pisa Medical School Hospital, Pisa, Italy
| | - Adriano Peris
- Regional Transplant Authority of Tuscany, Florence, Italy
| | - Daniela Campani
- Division of Pathology, University of Pisa Medical School Hospital, Pisa, Italy
| | - Giuseppina Basta
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Gianni Ciofani
- Smart Bio-Interfaces, Istituto Italiano di Tecnologia, Pontedera, Italy
| | - Davide Ghinolfi
- Division of Hepatic Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Pisa, Italy
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19
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Delivering siRNA Compounds During HOPE to Modulate Organ Function: A Proof-of-Concept Study in a Rat Liver Transplant Model. Transplantation 2022; 106:1565-1576. [PMID: 35581683 DOI: 10.1097/tp.0000000000004175] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Apoptosis contributes to the severity of ischemia-reperfusion injury (IRI), limiting the use of extended criteria donors in liver transplantation (LT). Machine perfusion has been proposed as a platform to administer specific therapies to improve graft function. Alternatively, the inhibition of genes associated with apoptosis during machine perfusion could alleviate IRI post-LT. The aim of the study was to investigate whether inhibition of an apoptosis-associated gene (FAS) using a small interfering RNA (siRNA) approach could alleviate IRI in a rat LT model. METHODS In 2 different experimental protocols, FASsiRNA (500 µg) was administered to rat donors 2 h before organ procurement, followed by 22 h of static cold storage, (SCS) or was added to the perfusate during 1 h of ex situ hypothermic oxygenated perfusion (HOPE) to livers previously preserved for 4 h in SCS. RESULTS Transaminase levels were significantly lower in the SCS-FASsiRNA group at 24 h post-LT. Proinflammatory cytokines (interleukin-2, C-X-C motif chemokine 10, tumor necrosis factor alpha, and interferon gamma) were significantly decreased in the SCS-FASsiRNA group, whereas the interleukin-10 anti-inflammatory cytokine was significantly increased in the HOPE-FASsiRNA group. Liver absorption of FASsiRNA after HOPE session was demonstrated by confocal microscopy; however, no statistically significant differences on the apoptotic index, necrosis levels, and FAS protein transcription between treated and untreated groups were observed. CONCLUSIONS FAS inhibition through siRNA therapy decreases the severity of IRI after LT in a SCS protocol; however the association of siRNA therapy with a HOPE perfusion model is very challenging. Future studies using better designed siRNA compounds and appropriate doses are required to prove the siRNA therapy effectiveness during liver HOPE liver perfusion.
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20
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Buchwald JE, Martins PN. Designer organs: The future of personalized transplantation. Artif Organs 2022; 46:180-190. [DOI: 10.1111/aor.14151] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Julianna E. Buchwald
- Division of Transplantation Department of Surgery University of Massachusetts Chan Medical School Worcester Massachusetts USA
- RNA Therapeutics Institute University of Massachusetts Chan Medical School Worcester Massachusetts USA
| | - Paulo N. Martins
- Division of Transplantation Department of Surgery University of Massachusetts Chan Medical School Worcester Massachusetts USA
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21
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Bonaccorsi-Riani E, Gillooly A, Brüggenwirth IMA, Martins PN. Delivery of genetic load during ex situ liver machine perfusion with potential for CRISPR-Cas9 gene editing: An innovative strategy for graft treatment. Hepatobiliary Pancreat Dis Int 2021; 20:503-505. [PMID: 33958293 DOI: 10.1016/j.hbpd.2021.04.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 04/13/2021] [Indexed: 02/05/2023]
Affiliation(s)
- Eliano Bonaccorsi-Riani
- Abdominal Transplant Unit, Cliniques Universitaires Saint Luc, Université Catholique de Louvain, Brussels, Belgium; Pôle de Chirurgie Expérimentale et Transplantation, Université Catholique de Louvain, Brussels, Belgium; Department of Surgery, Transplant Division, University of Massachusetts, Worcester-Massachusetts, USA
| | - Andrew Gillooly
- Department of Surgery, Transplant Division, University of Massachusetts, Worcester-Massachusetts, USA
| | - Isabel M A Brüggenwirth
- Department of Surgery, Transplant Division, University of Massachusetts, Worcester-Massachusetts, USA; Department of Surgery, Section of hepatobiliary surgery and liver transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Paulo N Martins
- Department of Surgery, Transplant Division, University of Massachusetts, Worcester-Massachusetts, USA.
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22
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van Beekum CJ, Vilz TO, Glowka TR, von Websky MW, Kalff JC, Manekeller S. Normothermic Machine Perfusion (NMP) of the Liver - Current Status and Future Perspectives. Ann Transplant 2021; 26:e931664. [PMID: 34426566 PMCID: PMC8400594 DOI: 10.12659/aot.931664] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 06/21/2021] [Indexed: 12/24/2022] Open
Abstract
A shortage of available organs for liver transplantation has led transplant surgeons and researchers to seek for innovative approaches in hepatoprotection and improvement of marginal allografts. The most exciting development in the past decade has been continuous mechanical perfusion of livers with blood or preservation solution to mitigate ischemia-reperfusion injury in contrast to the current standard of static cold storage. Two variations of machine perfusion have emerged in clinical practice. During hypothermic oxygenated perfusion the liver is perfused using a red blood cell-free perfusate at 2-10°C. In contrast, normothermic machine perfusion mimics physiologic liver perfusion using a red blood cell-based solution at 35.5-037.5°C, offering a multitude of potential advantages. Putative effects of normothermic perfusion include abrogation of hyperfibrinolysis after reperfusion and inflammation, glycogen repletion, and regeneration of adenosine triphosphate. Research in normothermic machine perfusion focuses on development of biomarkers predicting allograft quality and susceptibility to ischemia-reperfusion injury. Moreover, normothermic perfusion of marginal allografts allows for application of a variety of therapeutic interventions potentially enhancing organ quality. Both methods need to be subjected to translational investigation and evaluation in clinical trials. A clear advantage is transformation of an emergency procedure at night into a planned daytime surgery. Current clinical trials suggest that normothermic perfusion not only increases the use of hepatic allografts but is also associated with milder ischemia-reperfusion injury, resulting in a reduced risk of early allograft dysfunction and less biliary complications, including ischemic cholangiopathy, compared to static cold storage. The aim of this review is to give a concise overview of normothermic machine perfusion and its current applications, benefits, and possible advances in the future.
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23
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Ghinolfi D, Melandro F, Torri F, Martinelli C, Cappello V, Babboni S, Silvestrini B, De Simone P, Basta G, Del Turco S. Extended criteria grafts and emerging therapeutics strategy in liver transplantation. The unstable balance between damage and repair. Transplant Rev (Orlando) 2021; 35:100639. [PMID: 34303259 DOI: 10.1016/j.trre.2021.100639] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 07/10/2021] [Accepted: 07/12/2021] [Indexed: 02/07/2023]
Abstract
Due to increasing demand for donor organs, "extended criteria" donors are increasingly considered for liver transplantation, including elderly donors and donors after cardiac death. The grafts of this subgroup of donors share a major risk to develop significant features of ischemia reperfusion injury, that may eventually lead to graft failure. Ex-situ machine perfusion technology has gained much interest in liver transplantation, because represents both a useful tool for improving graft quality before transplantation and a platform for the delivery of therapeutics directly to the organ. In this review, we survey ongoing clinical evidences supporting the use of elderly and DCD donors in liver transplantation, and the underlying mechanistic aspects of liver aging and ischemia reperfusion injury that influence graft quality and transplant outcome. Finally, we highlight evidences in the field of new therapeutics to test in MP in the context of recent findings of basic and translational research.
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Affiliation(s)
- Davide Ghinolfi
- Division of Hepatic Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Via Paradisa 2, 56124 Pisa, Italy.
| | - Fabio Melandro
- Division of Hepatic Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Via Paradisa 2, 56124 Pisa, Italy
| | - Francesco Torri
- Division of Hepatic Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Via Paradisa 2, 56124 Pisa, Italy
| | - Caterina Martinelli
- Division of Hepatic Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Via Paradisa 2, 56124 Pisa, Italy
| | - Valentina Cappello
- Center for Nanotechnology Innovation@NEST, Istituto Italiano di Tecnologia, Piazza S. Silvestro 12, 56127 Pisa, Italy
| | - Serena Babboni
- Institute of Clinical Physiology, CNR San Cataldo Research Area, via Moruzzi 1, 56124 Pisa, Italy
| | - Beatrice Silvestrini
- Department of Surgical, Medical, Molecular Pathology, and Critical Area, University of Pisa, 56122 Pisa, Italy.
| | - Paolo De Simone
- Division of Hepatic Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Via Paradisa 2, 56124 Pisa, Italy
| | - Giuseppina Basta
- Institute of Clinical Physiology, CNR San Cataldo Research Area, via Moruzzi 1, 56124 Pisa, Italy
| | - Serena Del Turco
- Institute of Clinical Physiology, CNR San Cataldo Research Area, via Moruzzi 1, 56124 Pisa, Italy.
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24
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van Alem CMA, Metselaar JM, van Kooten C, Rotmans JI. Recent Advances in Liposomal-Based Anti-Inflammatory Therapy. Pharmaceutics 2021; 13:pharmaceutics13071004. [PMID: 34371695 PMCID: PMC8309101 DOI: 10.3390/pharmaceutics13071004] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 06/27/2021] [Accepted: 06/28/2021] [Indexed: 01/13/2023] Open
Abstract
Liposomes can be seen as ideal carriers for anti-inflammatory drugs as their ability to (passively) target sites of inflammation and release their content to inflammatory target cells enables them to increase local efficacy with only limited systemic exposure and adverse effects. Nonetheless, few liposomal formulations seem to reach the clinic. The current review provides an overview of the more recent innovations in liposomal treatment of rheumatoid arthritis, psoriasis, vascular inflammation, and transplantation. Cutting edge developments include the liposomal delivery of gene and RNA therapeutics and the use of hybrid systems where several liposomal bilayer features, or several drugs, are combined in a single formulation. The majority of the articles reviewed here focus on preclinical animal studies where proof-of-principle of an improved efficacy-safety ratio is observed when using liposomal formulations. A few clinical studies are included as well, which brings us to a discussion about the challenges of clinical translation of liposomal nanomedicines in the field of inflammatory diseases.
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Affiliation(s)
- Carla M. A. van Alem
- Department of Internal Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (C.M.A.v.A.); (C.v.K.)
| | - Josbert M. Metselaar
- Institute for Experimental Molecular Imaging, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany;
| | - Cees van Kooten
- Department of Internal Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (C.M.A.v.A.); (C.v.K.)
| | - Joris I. Rotmans
- Department of Internal Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (C.M.A.v.A.); (C.v.K.)
- Correspondence: ; Tel.: +31-(0)-7152-62148
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25
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Lembach Jahnsen H, Mergental H, Perera MTPR, Mirza DF. Ex-situ liver preservation with machine preservation. Curr Opin Organ Transplant 2021; 26:121-132. [PMID: 33650995 DOI: 10.1097/mot.0000000000000864] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
PURPOSE OF REVIEW To summarize key studies in liver preservation published over the last 3 years and evaluate benefits and limitations of the different perfusion techniques. Selected experimental applications that may be translated to the clinical use will be also discussed. RECENT FINDINGS Normothermic machine perfusion (NMP) has transitioned into clinical practice. Viability assessment is a reliable tool for clinical decision-making, and safety of the back-to-base approach has facilitated adoption of the technology. Data supporting well tolerated use of declined livers after NMP and new protocols selecting complex recipients aim to improve access to suitable organs. Hypothermic machine perfusion (HMP) is showing promising clinical results by decreasing biliary complications in recipients' receiving organs donated after circulatory death (DCD) and improving early graft function in extended criteria organs. Long-term data of HMP on DCD livers shows improved graft survival over standard SCS. Novel approaches utilizing sequential HMP--NMP or ischaemia-free preservation aim to improve outcomes of extended criteria organs. SUMMARY Machine perfusion for organ transplantation has become an established technique but the field is rapidly evolving. Ongoing research focuses on evaluation of the intervention efficacy and finding optimal indications to use each perfusion strategy according to graft type and clinical scenario.
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Affiliation(s)
- Hanns Lembach Jahnsen
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust (UHBFT), Birmingham
| | - Hynek Mergental
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust (UHBFT), Birmingham
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
| | - M Thamara P R Perera
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust (UHBFT), Birmingham
| | - Darius F Mirza
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust (UHBFT), Birmingham
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
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26
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Aufhauser DD, Foley DP. Beyond Ice and the Cooler: Machine Perfusion Strategies in Liver Transplantation. Clin Liver Dis 2021; 25:179-194. [PMID: 33978577 DOI: 10.1016/j.cld.2020.08.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Machine perfusion (MP) has emerged as a promising preservation technique to reduce the risks associated with transplant of high risk (steatotic, elderly, and donation after circulatory death) hepatic allografts. Multiple strategies for MP are under investigation. MP facilitates assessment of organ viability and enables liver-directed therapy before transplant. Clinical trials suggest MP may improve the use of hepatic allografts, mitigate ischemia-reperfusion injury, and reduce the incidences of early allograft dysfunction, biliary complications, and ischemic cholangiopathy. As MP sees more widespread use outside of trial settings, more investigation will be needed to establish optimal application of this technology.
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Affiliation(s)
- David D Aufhauser
- Department of Surgery, Division of Transplantation, University of Wisconsin, 600 Highland Avenue, MC 7375, Madison, WI 53792, USA
| | - David P Foley
- Department of Surgery, Division of Transplantation, University of Wisconsin, CSC H5/701, 600 Highland Avenue, Madison, WI 52792, USA.
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27
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Michelotto J, Gassner JMGV, Moosburner S, Muth V, Patel MS, Selzner M, Pratschke J, Sauer IM, Raschzok N. Ex vivo machine perfusion: current applications and future directions in liver transplantation. Langenbecks Arch Surg 2021; 406:39-54. [PMID: 33216216 PMCID: PMC7870621 DOI: 10.1007/s00423-020-02014-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 07/21/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Liver transplantation is the only curative treatment option for end-stage liver disease; however, its use remains limited due to a shortage of suitable organs. In recent years, ex vivo liver machine perfusion has been introduced to liver transplantation, as a means to expand the donor organ pool. PURPOSE To present a systematic review of prospective clinical studies on ex vivo liver machine perfusion, in order to assess current applications and highlight future directions. METHODS A systematic literature search of both PubMed and ISI web of science databases as well as the ClinicalTrials.gov registry was performed. RESULTS Twenty-one articles on prospective clinical trials on ex vivo liver machine perfusion were identified. Out of these, eight reported on hypothermic, eleven on normothermic, and two on sequential perfusion. These trials have demonstrated the safety and feasibility of ex vivo liver machine perfusion in both standard and expanded criteria donors. Currently, there are twelve studies enrolled in the clinicaltrials.gov registry, and these focus on use of ex vivo perfusion in extended criteria donors and declined organs. CONCLUSION Ex vivo liver machine perfusion seems to be a suitable strategy to expand the donor pool for liver transplantation and holds promise as a platform for reconditioning diseased organs.
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Affiliation(s)
- Julian Michelotto
- Charité - Universitätsmedizin Berlin, Department of Surgery, Experimental Surgery, corporate member of Freie Universität Berlin, Humboldt- Universität zu Berlin and Berlin Institute of Health, Campus Charité Mitte | Campus Virchow-Klinikum, Berlin, Germany
| | - Joseph M G V Gassner
- Charité - Universitätsmedizin Berlin, Department of Surgery, Experimental Surgery, corporate member of Freie Universität Berlin, Humboldt- Universität zu Berlin and Berlin Institute of Health, Campus Charité Mitte | Campus Virchow-Klinikum, Berlin, Germany
| | - Simon Moosburner
- Charité - Universitätsmedizin Berlin, Department of Surgery, Experimental Surgery, corporate member of Freie Universität Berlin, Humboldt- Universität zu Berlin and Berlin Institute of Health, Campus Charité Mitte | Campus Virchow-Klinikum, Berlin, Germany
| | - Vanessa Muth
- Charité - Universitätsmedizin Berlin, Department of Surgery, Experimental Surgery, corporate member of Freie Universität Berlin, Humboldt- Universität zu Berlin and Berlin Institute of Health, Campus Charité Mitte | Campus Virchow-Klinikum, Berlin, Germany
| | - Madhukar S Patel
- Department of Surgery, Abdominal Transplant and HPB Surgery, Ajmera Family Transplant Centre, Toronto General Hospital, Toronto, ON, Canada
| | - Markus Selzner
- Department of Surgery, Abdominal Transplant and HPB Surgery, Ajmera Family Transplant Centre, Toronto General Hospital, Toronto, ON, Canada
| | - Johann Pratschke
- Charité - Universitätsmedizin Berlin, Department of Surgery, Experimental Surgery, corporate member of Freie Universität Berlin, Humboldt- Universität zu Berlin and Berlin Institute of Health, Campus Charité Mitte | Campus Virchow-Klinikum, Berlin, Germany
| | - Igor M Sauer
- Charité - Universitätsmedizin Berlin, Department of Surgery, Experimental Surgery, corporate member of Freie Universität Berlin, Humboldt- Universität zu Berlin and Berlin Institute of Health, Campus Charité Mitte | Campus Virchow-Klinikum, Berlin, Germany
| | - Nathanael Raschzok
- Charité - Universitätsmedizin Berlin, Department of Surgery, Experimental Surgery, corporate member of Freie Universität Berlin, Humboldt- Universität zu Berlin and Berlin Institute of Health, Campus Charité Mitte | Campus Virchow-Klinikum, Berlin, Germany.
- Department of Surgery, Abdominal Transplant and HPB Surgery, Ajmera Family Transplant Centre, Toronto General Hospital, Toronto, ON, Canada.
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Gao J, He K, Xia Q, Zhang J. Research progress on hepatic machine perfusion. Int J Med Sci 2021; 18:1953-1959. [PMID: 33850464 PMCID: PMC8040389 DOI: 10.7150/ijms.56139] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 02/12/2021] [Indexed: 01/08/2023] Open
Abstract
Nowadays, liver transplantation is the most effective treatment for end-stage liver disease. However, the increasing imbalance between growing demand for liver transplantation and the shortage of donor pool restricts the development of liver transplantation. How to expand the donor pool is a significant problem to be solved clinically. Many doctors have devoted themselves to marginal grafting, which introduces livers with barely passable quality but a high risk of transplant failure into the donor pool. However, existing common methods of preserving marginal grafts lead to both high risk of postoperative complications and high mortality. The application of machine perfusion allows surgeons to make marginal livers meet the standard criteria for transplant, which shows promising prospect in preserving and repairing donor livers and improving ischemia reperfusion injury. This review summarizes the progress of recent researches on hepatic machine perfusion.
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Affiliation(s)
- Junda Gao
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kang He
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jianjun Zhang
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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29
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Immunological organ modification during Ex Vivo machine perfusion: The future of organ acceptance. Transplant Rev (Orlando) 2020; 35:100586. [PMID: 33876730 DOI: 10.1016/j.trre.2020.100586] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 10/01/2020] [Accepted: 10/14/2020] [Indexed: 12/27/2022]
Abstract
Ex vivo machine perfusion (EVMP) has gained revitalized interest in recent years due to the increasing use of marginal organs which poorly tolerate the standard preservation method static cold storage (SCS). EVMP improves on SCS in a number of ways, most notably by the potential for reconditioning of the donor organ prior to transplantation without the ethical concerns associated with organ modulation before procurement. Immunomodulatory therapies administered during EVMP can influence innate and adaptive immune responses to reduce production of inflammatory molecules and polarize tissue-resident immune cells to a regulatory phenotype. The targeted inhibition of an inflammatory response can reduce ischemia-reperfusion injury following organ reoxygenation and therefore reduce incidence of graft dysfunction and rejection. Numerous approaches to modulate the inflammatory response have been applied in experimental models, with the ultimate goal of clinical translatability. Strategies to target the innate immune system include inhibiting inflammatory signaling pathways, upregulating anti-inflammatory mediators, and decreasing mitochondrial damage while those which target the adaptive immune system include mesenchymal stromal cells. Inhibitory RNA approaches target both the innate and adaptive immune systems with a focus on MHC knock-down. Future studies may address issues of therapeutic agent delivery through use of nanoparticles and explore novel strategies such as targeting co-inhibitory molecules to educate T-cells to a tolerogenic state. In this review, we summarize the cellular and acellular contributors to allograft dysfunction and rejection, discuss the strategies which have been employed pre-clinically during EVMP to modulate the donor organ immune environment, and suggest future directions for immunomodulatory EVMP studies.
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Abstract
A recent technological advance that shows promise for applications in health care, including transplantation medicine, is the implementation of nanoparticles. Nanoparticles can be composed of a variety of organic or inorganic materials and confer many advantages over conventional treatments available, such as low toxicity, low-effective dosage required, and a high degree of manipulability. Although also used for imaging and diagnostics, nanoparticles' utility as a drug or genetic delivery system is of particular interest in transplantation medicine. Currently, researchers are exploring options to integrate nanoparticles into both diagnostics and therapy for both grafts ex-situ before transplantation and for patients following transplantation. These studies have demonstrated that nanoparticles can mitigate damage to organs and patients through a large variety of mechanisms-ranging from the induction of cellular genetic changes to the enhancement of immunosuppressive drug delivery. Specifically, with the advent of machine perfusion preservation ex vivo, treatment of the graft became a very attractive approach and nanoparticles have great potential. However, before nanoparticles can be translated into clinical use, their short-term and long-term toxicity must be thoroughly characterized, especially with regards to their interactions with other biological molecules present in the human body.
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Normothermic Ex Vivo Liver Perfusion Prevents Intrahepatic Platelet Sequestration After Liver Transplantation. Transplantation 2020; 104:1177-1186. [PMID: 32091485 DOI: 10.1097/tp.0000000000003194] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The detrimental role of platelets in sinusoidal endothelial cell (SEC) injury during liver transplantation (LT) has been previously addressed after static cold storage (SCS), however, it is currently unknown after normothermic ex vivo liver perfusion (NEVLP). METHODS Pig LT was performed with livers from heart-beating donors or donation after circulatory death (DCD) donors subjected to SCS or NEVLP (n = 5/group). RESULTS All pigs except for 1 (DCD-SCS-group) survived 4 days. The heart-beating donor- and DCD-NEVLP-groups showed significantly lower aspartate transaminase-levels compared with the SCS-groups 3 hours post-LT (P = 0.006), on postoperative day (POD) 2 (P = 0.005), POD3 (P = 0.007), and on POD4 (P = 0.012). Post-LT total platelet count recovered faster in the NEVLP than in the SCS-groups at 12 hours (P = 0.023) and 24 hours (P = 0.0038). Intrahepatic sequestration of platelets was significantly higher in the SCS-groups 3 hours postreperfusion and correlated with severity of SEC injury. In both SCS-groups, levels of tumor growth factor-β were higher 3 hours post-LT, on POD1 and on POD3. Moreover, platelet factor 4 levels and platelet-derived extracellular vesicles were increased in the SCS-groups. Hyaluronic acid levels were significantly higher in the SCS-groups, indicating a higher grade of endothelial cell dysfunction. Platelet inhibition achieved by pretreatment with clopidogrel (n = 3) partly reversed the detrimental effects on SEC injury and therefore provided further evidence of the important role of platelets in ischemia/reperfusion injury and SEC injury. CONCLUSIONS Normothermic perfusion of liver grafts before transplantation effectively reduced platelet aggregation and SEC injury, which translated into an improved posttransplant organ function.
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Abstract
Because of the high demand of organs, the usage of marginal grafts has increased. These marginal organs have a higher risk of developing ischemia-reperfusion injury, which can lead to posttransplant complications. Ex situ machine perfusion (MP), compared with the traditional static cold storage, may better protect these organs from ischemia-reperfusion injury. In addition, MP can also act as a platform for dynamic administration of pharmacological agents or gene therapy to further improve transplant outcomes. Numerous therapeutic agents have been studied under both hypothermic (1-8°C) and normothermic settings. Here, we review all the therapeutics used during MP in different organ systems (lung, liver, kidney, heart). The major categories of therapeutic agents include vasodilators, mesenchymal stem cells, antiinflammatory agents, antiinfection agents, siRNA, and defatting agents. Numerous animal and clinical studies have examined MP therapeutic agents, some of which have even led to the successful reconditioning of discarded grafts. More clinical studies, especially randomized controlled trials, will need to be conducted in the future to solidify these promising results and to define the role of MP therapeutic agents in solid organ transplantation.
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Martins PN, Buchwald JE, Mergental H, Vargas L, Quintini C. The role of normothermic machine perfusion in liver transplantation. Int J Surg 2020; 82S:52-60. [PMID: 32417462 DOI: 10.1016/j.ijsu.2020.05.026] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 04/14/2020] [Accepted: 05/11/2020] [Indexed: 02/07/2023]
Abstract
To expand the donor pool of suitable organs for transplantation, there is an increased interest in utilizing extended criteria donor grafts (ECD). Ex-situ machine perfusion has shown to be a promising new modality in the organ preservation field to reduce injury and recover ECD liver grafts. Machine perfusion (MP) is considered a significant improvement in the field of transplantation over the past 20 years. Normothermic machine perfusion has entered the clinical arena in the last decade and has shown promising results to improve the quality of marginal organs and to increase the pool of liver grafts. It allows assessment of viability and function of grafts prior to transplantation. In addition, it has the potential to serve as a platform for pharmacologic organ treatment and graft optimization. Machine perfusion moved from the experimental phase to a more mature phase after safety was confirmed by initial clinical trials. Now, it is time to confirm its superiority and cost-effectiveness before a broader clinical use. In this paper we review the history, current status including outcomes of all clinical trials, limitations, and future trends of normothermic machine preservation.
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Affiliation(s)
- Paulo N Martins
- University of Massachusetts, Dept of Surgery, Transplant Division, Worcester, MA, USA.
| | - Julianna E Buchwald
- University of Massachusetts, Dept of Surgery, Transplant Division, Worcester, MA, USA
| | - Hynek Mergental
- Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Luciano Vargas
- Dept of Surgery, Transplant Division, University of Nebraska Medical Center, USA
| | - Cristiano Quintini
- Dept of Surgery, Transplant Division, Cleveland Clinic, Cleveland, OH, USA
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Bonaccorsi-Riani E, Brüggenwirth IMA, Buchwald JE, Iesari S, Martins PN. Machine Perfusion: Cold versus Warm, versus Neither. Update on Clinical Trials. Semin Liver Dis 2020; 40:264-281. [PMID: 32557478 DOI: 10.1055/s-0040-1713118] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Machine perfusion (MP) preservation is potentially one of the most significant improvements in the field of liver transplantation in the last 20 years, and it has been considered a promising strategy for improved preservation and ex situ evaluation of extended criteria donor (ECD) organs. However, MP preservation adds significant cost and logistical considerations to liver transplantation. MP protocols are mainly classified according to the perfusion temperature with hypothermic machine perfusion (HMP) and normothermic machine perfusion (NMP) being the two categories most studied so far. After extensive preclinical work, MP entered the clinical setting, and there are now several studies that demonstrated feasibility and safety. However, because of the limited quality of clinical trials, there is no compelling evidence of superiority in preservation quality, and liver MP is still considered experimental in most countries. MP preservation is moving to a more mature phase, where ongoing and future studies will bring new evidence in order to confirm their superiority in terms of clinical outcomes, organ utilization, and cost-effectiveness. Here, we present an overview of all preclinical MP studies using discarded human livers and liver MP clinical trials, and discuss their results. We describe the different perfusion protocols, pitfalls in MP study design, and provide future perspectives. Recent trials in liver MP have revealed unique challenges beyond those seen in most clinical studies. Randomized trials, correct trial design, and interpretation of data are essential to generate the data necessary to prove if MP will be the new gold standard method of liver preservation.
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Affiliation(s)
- E Bonaccorsi-Riani
- Abdominal Transplant Unit, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.,Pôle de Chirurgie Expérimentale et Transplantation, Université Catholique de Louvain, Brussels, Belgium
| | - I M A Brüggenwirth
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - J E Buchwald
- Division of Transplant, Department of Surgery, UMass Memorial Medical Center, University of Massachusetts, Worcester, Massachusetts
| | - S Iesari
- Pôle de Chirurgie Expérimentale et Transplantation, Université Catholique de Louvain, Brussels, Belgium.,Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - P N Martins
- Division of Transplant, Department of Surgery, UMass Memorial Medical Center, University of Massachusetts, Worcester, Massachusetts
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Piotrowski-Daspit AS, Kauffman AC, Bracaglia LG, Saltzman WM. Polymeric vehicles for nucleic acid delivery. Adv Drug Deliv Rev 2020; 156:119-132. [PMID: 32585159 PMCID: PMC7736472 DOI: 10.1016/j.addr.2020.06.014] [Citation(s) in RCA: 121] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 06/09/2020] [Accepted: 06/13/2020] [Indexed: 12/20/2022]
Abstract
Polymeric vehicles are versatile tools for therapeutic gene delivery. Many polymers-when assembled with nucleic acids into vehicles-can protect the cargo from degradation and clearance in vivo, and facilitate its transport into intracellular compartments. Design options in polymer synthesis yield a comprehensive range of molecules and resulting vehicle formulations. These properties can be manipulated to achieve stronger association with nucleic acid cargo and cells, improved endosomal escape, or sustained delivery depending on the application. Here, we describe current approaches for polymer use and related strategies for gene delivery in preclinical and clinical applications. Polymer vehicles delivering genetic material have already achieved significant therapeutic endpoints in vitro and in animal models. From our perspective, with preclincal assays that better mimic the in vivo environment, improved strategies for target specificity, and scalable techniques for polymer synthesis, the impact of this therapeutic approach will continue to expand.
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Affiliation(s)
| | - Amy C Kauffman
- Department of Biomedical Engineering, Yale University, New Haven, CT 06511, United States of America; Corning Life Sciences, Kennebunk, ME 04043, United States of America
| | - Laura G Bracaglia
- Department of Biomedical Engineering, Yale University, New Haven, CT 06511, United States of America
| | - W Mark Saltzman
- Department of Biomedical Engineering, Yale University, New Haven, CT 06511, United States of America; Department of Chemical & Environmental Engineering, Yale University, New Haven, CT 06511, United States of America; Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, United States of America; Department of Dermatology, Yale School of Medicine, New Haven, CT 06510, United States of America.
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Dengu F, Abbas SH, Ebeling G, Nasralla D. Normothermic Machine Perfusion (NMP) of the Liver as a Platform for Therapeutic Interventions during Ex-Vivo Liver Preservation: A Review. J Clin Med 2020; 9:jcm9041046. [PMID: 32272760 PMCID: PMC7231144 DOI: 10.3390/jcm9041046] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 03/17/2020] [Accepted: 03/31/2020] [Indexed: 12/18/2022] Open
Abstract
Liver transplantation is increasingly dependent on the use of extended criteria donors (ECD) to increase the organ donor pool and address rising demand. This has necessitated the adoption of innovative technologies and strategies to protect these higher-risk grafts from the deleterious effects of traditional preservation and ischaemia reperfusion injury (IRI). The advent of normothermic machine perfusion (NMP) and rapid growth in the clinical adoption of this technology has accelerated efforts to utilise NMP as a platform for therapeutic intervention to optimise donor livers. In this review we will explore the emerging preclinical data related to ameliorating the effects of IRI, protecting the microcirculation and reducing the immunogenicity of donor organs during NMP. Exploiting the window of opportunity afforded by NMP, whereby the liver can be continuously supported and functionally assessed while therapies are directly delivered during the preservation period, has clear logistical and theoretical advantages over current preservation methods. The clinical translation of many of the therapeutic agents and strategies we will describe is becoming more feasible with widespread adaptation of NMP devices and rapid advances in molecular biology and gene therapy, which have substantially improved the performance of these agents. The delivery of novel therapeutics during NMP represents one of the new frontiers in transplantation research and offers real potential for successfully tackling fundamental challenges in transplantation such as IRI.
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Affiliation(s)
- Fungai Dengu
- Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX1 2JD, UK; (S.H.A.); (G.E.); (D.N.)
- Correspondence:
| | - Syed Hussain Abbas
- Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX1 2JD, UK; (S.H.A.); (G.E.); (D.N.)
| | - Georg Ebeling
- Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX1 2JD, UK; (S.H.A.); (G.E.); (D.N.)
| | - David Nasralla
- Oxford Transplant Centre, Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX1 2JD, UK; (S.H.A.); (G.E.); (D.N.)
- Department of Hepatopancreatobiliary and Liver Transplant Surgery, Royal Free Hospital, Pond St, Hampstead, London NW3 2QG, UK
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Czigany Z, Lurje I, Schmelzle M, Schöning W, Öllinger R, Raschzok N, Sauer IM, Tacke F, Strnad P, Trautwein C, Neumann UP, Fronek J, Mehrabi A, Pratschke J, Schlegel A, Lurje G. Ischemia-Reperfusion Injury in Marginal Liver Grafts and the Role of Hypothermic Machine Perfusion: Molecular Mechanisms and Clinical Implications. J Clin Med 2020; 9:E846. [PMID: 32244972 PMCID: PMC7141496 DOI: 10.3390/jcm9030846] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/09/2020] [Accepted: 03/11/2020] [Indexed: 12/19/2022] Open
Abstract
Ischemia-reperfusion injury (IRI) constitutes a significant source of morbidity and mortality after orthotopic liver transplantation (OLT). The allograft is metabolically impaired during warm and cold ischemia and is further damaged by a paradox reperfusion injury after revascularization and reoxygenation. Short-term and long-term complications including post-reperfusion syndrome, delayed graft function, and immune activation have been associated with IRI. Due to the current critical organ shortage, extended criteria grafts are increasingly considered for transplantation, however, with an elevated risk to develop significant features of IRI. In recent years, ex vivo machine perfusion (MP) of the donor liver has witnessed significant advancements. Here, we describe the concept of hypothermic (oxygenated) machine perfusion (HMP/HOPE) approaches and highlight which allografts may benefit from this technology. This review also summarizes clinical applications and the main aspects of ongoing randomized controlled trials on hypothermic perfusion. The mechanistic aspects of IRI and hypothermic MP-which include tissue energy replenishment, optimization of mitochondrial function, and the reduction of oxidative and inflammatory damage following reperfusion-will be comprehensively discussed within the context of current preclinical and clinical evidence. Finally, we highlight novel trends and future perspectives in the field of hypothermic MP in the context of recent findings of basic and translational research.
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Affiliation(s)
- Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (Z.C.); (U.P.N.)
| | - Isabella Lurje
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Moritz Schmelzle
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Wenzel Schöning
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Robert Öllinger
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Nathanael Raschzok
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Igor M. Sauer
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany;
| | - Pavel Strnad
- Department of Gastroenterology, Metabolic Disorders and Intensive Care, University Hospital RWTH Aachen, 52074 Aachen, Germany; (P.S.); (C.T.)
| | - Christian Trautwein
- Department of Gastroenterology, Metabolic Disorders and Intensive Care, University Hospital RWTH Aachen, 52074 Aachen, Germany; (P.S.); (C.T.)
| | - Ulf Peter Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (Z.C.); (U.P.N.)
| | - Jiri Fronek
- Department of Transplant Surgery, Institute for Clinical and Experimental Medicine, 140 21 Prague, Czech Republic;
| | - Arianeb Mehrabi
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, 69120 Heidelberg, Germany;
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
| | - Andrea Schlegel
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, UK;
| | - Georg Lurje
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, 52074 Aachen, Germany; (Z.C.); (U.P.N.)
- Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum—Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; (I.L.); (M.S.); (W.S.); (R.Ö.); (N.R.); (I.M.S.); (J.P.)
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Buchwald JE, Xu J, Bozorgzadeh A, Martins PN. Therapeutics administered during ex vivo liver machine perfusion: An overview. World J Transplant 2020; 10:1-14. [PMID: 32110510 PMCID: PMC7031625 DOI: 10.5500/wjt.v10.i1.1] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 10/26/2019] [Accepted: 12/06/2019] [Indexed: 02/06/2023] Open
Abstract
Although the use of extended criteria donors has increased the pool of available livers for transplant, it has also introduced the need to develop improved methods of protection against ischemia-reperfusion injury (IRI), as these "marginal" organs are particularly vulnerable to IRI during the process of procurement, preservation, surgery, and post-transplantation. In this review, we explore the current basic science research investigating therapeutics administered during ex vivo liver machine perfusion aimed at mitigating the effects of IRI in the liver transplantation process. These various categories of therapeutics are utilized during the perfusion process and include invoking the RNA interference pathway, utilizing defatting cocktails, and administering classes of agents such as vasodilators, anti-inflammatory drugs, human liver stem cell-derived extracellular vesicles, and δ-opioid agonists in order to reduce the damage of IRI. Ex vivo machine perfusion is an attractive alternative to static cold storage due to its ability to continuously perfuse the organ, effectively deliver substrates and oxygen required for cellular metabolism, therapeutically administer pharmacological or cytoprotective agents, and continuously monitor organ viability during perfusion. The use of administered therapeutics during machine liver perfusion has demonstrated promising results in basic science studies. While novel therapeutic approaches to combat IRI are being developed through basic science research, their use in clinical medicine and treatment in patients for liver transplantation has yet to be explored.
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Affiliation(s)
- Julianna E Buchwald
- Division of Transplantation, Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01655, United States
| | - Jing Xu
- Division of Transplantation, Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01655, United States
| | - Adel Bozorgzadeh
- Division of Transplantation, Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01655, United States
| | - Paulo N Martins
- Division of Transplantation, Department of Surgery, University of Massachusetts Medical School, Worcester, MA 01655, United States
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Bellini MI, Yiu J, Nozdrin M, Papalois V. The Effect of Preservation Temperature on Liver, Kidney, and Pancreas Tissue ATP in Animal and Preclinical Human Models. J Clin Med 2019; 8:1421. [PMID: 31505880 PMCID: PMC6780500 DOI: 10.3390/jcm8091421] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 08/30/2019] [Accepted: 09/02/2019] [Indexed: 02/06/2023] Open
Abstract
The recent advances in machine perfusion (MP) technology involve settings ranging between hypothermic, subnormothermic, and normothermic temperatures. Tissue level adenosine triphosphate (ATP) is a long-established marker of viability and functionality and is universal for all organs. In the midst of a growing number of complex clinical parameters for the quality assessment of graft prior to transplantation, a revisit of ATP may shed light on the underlying reconditioning mechanisms of different perfusion temperatures in the form of restoration of metabolic and energy status. This article aims to review and critically analyse animal and preclinical human studies (discarded grafts) during MP of three abdominal organs (liver, kidney, and pancreas) in which ATP was a primary endpoint. A selective review of recent novel reconditioning approaches relevant to mitigation of graft ischaemia-reperfusion injury via MP and for different perfusion temperatures was also conducted. With a current reiterated interest for oxygenation during MP, a re-introduction of tissue ATP levels may be valuable for graft viability assessment prior to transplantation. Further studies may help delineate the benefits of selective perfusion temperatures on organs viability.
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Affiliation(s)
| | - Janice Yiu
- School of Medicine, University College London, London WC1E 6BT, UK
| | - Mikhail Nozdrin
- School of Medicine, Imperial College London, London SW72AZ, UK
| | - Vassilios Papalois
- Renal and Transplant Directorate, Imperial College Healthcare NHS Trust, London W120HS, UK
- Department of Surgery and Cancer, Imperial College London, London SW72AZ, UK
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Abstract
PURPOSE OF REVIEW Pancreas transplantation enables complete patient independence from exogenous insulin administration and increases both patient survival and quality of life. Despite this, there has been a decline in pancreas transplantation for the past 20 years, influenced by changing donor demographics with more high-risk extended criteria (ECD) and donation after cardiac death (DCD) donors. This review discusses whether the advent of machine perfusion (MP), if extended to the pancreas, can increase the pool of suitable donor organs. RECENT FINDINGS Hypothermic and normothermic MP, as forms of preservation deemed superior to cold storage for high-risk kidney and liver donor organs, have opened the avenue for translation of this work into the pancreas. Recent experimental models of porcine and human ex-vivo pancreatic MP are promising. Applications of MP to the pancreas however need refinement-focusing on perfusion protocols and viability assessment tools. Emerging research shows pancreatic MP can potentially offer superior preservation capacity, the ability to both resuscitate and manipulate organs, and assess functional and metabolic organ viability. The future of MP will lie in organ assessment and resuscitation after retrieval, where ultimately organs initially considered high risk and unsuitable for transplantation will be optimised and transformed, making them then available for clinical use, thus increasing the pool of suitably viable pancreata for transplantation.
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Affiliation(s)
- Karim Hamaoui
- Department of Surgery, Imperial College London, London, UK
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